Numerous utilities and uses of cyclic depsipeptides are known in pharmacology. As an example, depsipeptides disclosed in WO 2009/024527 are useful for the treatment of various diseases.
For example, the compound of the formula A
mentioned in WO 2009/024527 is useful for the treatment and/or prevention of inflammatory and/or hyperproliferative and pruritic skin diseases, for example atopic dermatitis, psoriasis, pustular psoriasis, rosacea, keloids, hypertrophic scars, acne, Netherton's syndrome or other pruritic dermatoses such as prurigo nodularis, unspecified itch of the elderly as well as other diseases with epithelial barrier dysfunction such as aged skin. This compound is also named “Compound A” hereinafter.
Other cyclic depsipeptides, such as BN920, formerly isolated from the cyanobacterium Nostoc, was isolated also from Microcystis. Nostopeptin (BN920) inhibited chymotrypsin with an IC50 value of 31 nM (see J. Nat. Prod. 68(9), 1324-7 (2005)). It has formula B:

These compounds can be produced by fermentation (e.g. using Chondromyces croactus, myxobacteria) along with other depsipeptides comprising the so-called ahp-substructure (ahp: 3-amino-6-hydroxy-piperidin-2-one) and the corresponding dehydro-ahp substructure (dehydro-ahp: 3-amino-3,4-dihydro-1H-pyridin-2-one), also called “dehydrate” herein, respectively. Therefore, the yield of fermentation with regard to any single of these compounds is up to now rather low and cannot yet allow the manufacture of amounts sufficient on an industrial or even pilot scale.
Analogous compounds have been synthesized by solution phase synthesis, however, with poor yield and low efficiency.
The present invention therefore aims at providing a new method of manufacture allowing minimizing or removing the mentioned disadvantages.